8-132888417-G-T

Variant names:

• chr8-132888417-G-T
• rs2229843
• NM_003235.5:c.2610G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003235.5(TG):​c.2610G>T​(p.Gln870His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00453 in 1,613,570 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (34 hom.)
• Consequence: TG NM_003235.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 1.64
• Publications: 6 publications found

Genes affected

TG (HGNC:11764): (thyroglobulin) Thyroglobulin (Tg) is a glycoprotein homodimer produced predominantly by the thryroid gland. It acts as a substrate for the synthesis of thyroxine and triiodothyronine as well as the storage of the inactive forms of thyroid hormone and iodine. Thyroglobulin is secreted from the endoplasmic reticulum to its site of iodination, and subsequent thyroxine biosynthesis, in the follicular lumen. Mutations in this gene cause thyroid dyshormonogenesis, manifested as goiter, and are associated with moderate to severe congenital hypothyroidism. Polymorphisms in this gene are associated with susceptibility to autoimmune thyroid diseases (AITD) such as Graves disease and Hashimoto thryoiditis. [provided by RefSeq, Nov 2009]

TG Gene-Disease associations (from GenCC):

• thyroid dyshormonogenesis 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05794525).
• BP6: Variant 8-132888417-G-T is Benign according to our data. Variant chr8-132888417-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12690.
• BS2: High Homozygotes in GnomAdExome4 at 34 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003235.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	NM_003235.5	MANE Select	c.2610G>T	p.Gln870His	missense	Exon 10 of 48	NP_003226.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	ENST00000220616.9	TSL:1 MANE Select	c.2610G>T	p.Gln870His	missense	Exon 10 of 48	ENSP00000220616.4

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 454 AN: 152194 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00461

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00306 AC: 768 AN: 251104 AF XY: 0.00333

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.00436

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00469 AC: 6848 AN: 1461258 Hom.: 34 Cov.: 38 AF XY: 0.00467 AC XY: 3396 AN XY: 726802

African (AFR) AF: 0.000896 AC: 30 AN: 33474

American (AMR) AF: 0.00264 AC: 118 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00349 AC: 301 AN: 86228

European-Finnish (FIN) AF: 0.00195 AC: 104 AN: 53414

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.00547 AC: 6079 AN: 1111502

Other (OTH) AF: 0.00341 AC: 206 AN: 60378

GnomAD4 genome AF: 0.00298 AC: 454 AN: 152312 Hom.: 1 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74470

African (AFR) AF: 0.00101 AC: 42 AN: 41558

American (AMR) AF: 0.00333 AC: 51 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4818

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00462 AC: 314 AN: 68036

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00346 Hom.: 3

Bravo AF: 0.00281

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00324 AC: 393

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00421

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Iodotyrosyl coupling defect Uncertain:1 Benign:1

Sep 01, 2005

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

not provided Benign:2

Jun 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TG: BP4, BS2

Premature ovarian failure Uncertain:1

Apr 22, 2019

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

This variant was identified as homozygous in a female individual with hypergonadotropic hypogonadism.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.6
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.63		Gain of catalytic residue at L872 (P = 0.0918)
MVP		0.82
MPC		0.34
ClinPred		0.030	T
GERP RS		3.1
Varity_R		0.22
gMVP		0.72
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2229843; hg19: chr8-133900662; COSMIC: COSV105016342;